Total Syntheses of (+)-Polygalolide A and (+)-Polygalolide B: Elucidation of the Absolute Stereochemistry and Biogenetic Implications
Dr. Yukihito Sugano
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorDr. Fumiaki Kikuchi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorAkinori Toita
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorCorresponding Author
Prof. Dr. Seiichi Nakamura
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Present address: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603 (Japan)
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981Search for more papers by this authorCorresponding Author
Prof. Dr. Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981Search for more papers by this authorDr. Yukihito Sugano
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorDr. Fumiaki Kikuchi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorAkinori Toita
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Search for more papers by this authorCorresponding Author
Prof. Dr. Seiichi Nakamura
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Present address: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603 (Japan)
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981Search for more papers by this authorCorresponding Author
Prof. Dr. Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan), Fax: (+81) 11-706-4981Search for more papers by this authorGraphical Abstract
Full control: Stereochemical insights into the biogenesis of polygalolides A and B have been provided by the stereocontrolled total synthesis of these natural products (see scheme), wherein the key steps include a highly diastereoselective hetero-Michael reaction, a [Rh2(OAc)4]-catalyzed carbonyl ylide formation/1,3-dipolar cycloaddition, and a Mukaiyama aldol-type reaction.
Abstract
The total syntheses of (+)-polygalolide A and (+)-polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a [Rh2(OAc)4]-catalyzed carbonyl ylide formation/intramolecular 1,3-dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol-type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero-Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3 % overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a [5+2] cycloaddition between a fructose-derived oxypyrylium zwitterion with an isoprene derivative.
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References
- 1W. Ma, X. Wei, T. Ling, H. Xie, W. Zhou, J. Nat. Prod. 2003, 66, 441–443.
- 2Miyase and co-workers reported the isolation of 16 saponins from the roots of Polygala fallax Hemsl., see: D. Zhang, T. Miyase, M. Kuroyanagi, K. Umehara, H. Noguchi, Chem. Pharm. Bull. 1996, 44, 2092–2099.
- 3J. R. Dimmock, N. M. Kandepu, A. J. Nazarali, T. P. Kowalchuk, N. Motaganahalli, J. W. Quail, P. A. Mykytiuk, G. F. Audette, L. Prasad, P. Perjési, T. M. Allen, C. L. Santos, J. Szydlowski, E. De Clercq, J. Balzarini, J. Med. Chem. 1999, 42, 1358–1366 and references therein.
- 4M. Adachi, H. Yamada, M. Isobe, T. Nishikawa, Org. Lett. 2011, 13, 6532–6535.
- 5S. Nakamura, Y. Sugano, F. Kikuchi, S. Hashimoto, Angew. Chem. 2006, 118, 6682–6685;
- 6A. Padwa, G. E. Fryxell, L. Zhi, J. Am. Chem. Soc. 1990, 112, 3100–3109.
- 7For reviews, see:
- 7aA. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223–269;
- 7bM. C. McMills, D. Wright, in Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products (Eds.: ), John Wiley & Sons, New York, 2002, pp. 253–314;
- 7cG. Mehta, S. Muthusamy, Tetrahedron 2002, 58, 9477–9504;
- 7dA. Padwa, Helv. Chim. Acta 2005, 88, 1357–1374.
- 8For total syntheses of natural products by a carbonyl ylide cycloaddition strategy, see:
- 8aA. Padwa, R. L. Chinn, L. Zhi, Tetrahedron Lett. 1989, 30, 1491–1494;
- 8bF. R. Kinder, Jr., K. W. Bair, J. Org. Chem. 1994, 59, 6965–6967;
- 8cA. Padwa, M. A. Brodney, J. P. Marino, Jr., S. M. Sheehan, J. Org. Chem. 1997, 62, 78–87;
- 8dC. S. Straub, A. Padwa, Org. Lett. 1999, 1, 83–85;
- 8eJ. L. Wood, B. D. Thompson, N. Yusuff, D. A. Pflum, M. S. P. Matthäus, J. Am. Chem. Soc. 2001, 123, 2097–2098;
- 8fD. M. Hodgson, T. D. Avery, A. C. Donohue, Org. Lett. 2002, 4, 1809–1811;
- 8gS. Nakamura, Y. Hirata, T. Kurosaki, M. Anada, O. Kataoka, S. Kitagaki, S. Hashimoto, Angew. Chem. 2003, 115, 5509–5513;
- 8hD. M. Hodgson, F. Le Strat, T. D. Avery, A. C. Donohue, T. Brückl, J. Org. Chem. 2004, 69, 8796–8803;
- 8iT. Graening, V. Bette, J. Neudorfl, J. Lex, H.-G. Schmalz, Org. Lett. 2005, 7, 4317–4320;
- 8jJ. M. Mejía-Oneto, A. Padwa, Org. Lett. 2006, 8, 3275–3278;
- 8kZ. Geng, B. Chen, P. Chiu, Angew. Chem. 2006, 118, 6343–6347;
- 8lY. Hirata, S. Nakamura, N. Watanabe, O. Kataoka, T. Kurosaki, M. Anada, S. Kitagaki, M. Shiro, S. Hashimoto, Chem. Eur. J. 2006, 12, 8898–8925;
- 8mD. B. England, A. Padwa, Org. Lett. 2007, 9, 3249–3252;
- 8nS. K. Lam, P. Chiu, Chem. Eur. J. 2007, 13, 9589–9599;
- 8oJ. M. Mejía-Oneto, A. Padwa, Helv. Chim. Acta 2008, 91, 285–302;
- 8pC. H. Kim, K. P. Jang, S. Y. Choi, Y. K. Chung, E. Lee, Angew. Chem. 2008, 120, 4073–4075;
- 8qD. B. England, A. Padwa, J. Org. Chem. 2008, 73, 2792–2802;
- 8rN. Shimada, T. Hanari, Y. Kurosaki, K. Takeda, M. Anada, H. Nambu, M. Shiro, S. Hashimoto, J. Org. Chem. 2010, 75, 6039–6042;
- 8sN. Shimada, T. Hanari, Y. Kurosaki, M. Anada, H. Nambu, S. Hashimoto, Tetrahedron Lett. 2010, 51, 6572–6575. For reviews, see:
- 8tA. Padwa, Chem. Soc. Rev. 2009, 38, 3072–3081;
- 8uA. Padwa, Tetrahedron 2011, 67, 8057–8072.
- 9M. Y. H. Wong, G. R. Gray, J. Am. Chem. Soc. 1978, 100, 3548–3553. Using literature procedures, alcohol 8 could be prepared from D-arabinose on a 25 g scale in 65 % yield over four steps in our hands.
- 10M. J. Palmer, J. C. Danilewicz, H. Vuong, Synlett 1994, 171–172.
- 11R. M. Lemieux, P. N. Devine, M. F. Mechelke, A. I. Meyers, J. Org. Chem. 1999, 64, 3585–3591.
- 12G. A. Russell, L. A. Ochrymowycz, J. Org. Chem. 1969, 34, 3618–3624.
- 13
- 13aB. O. Lindgren, T. Nilsson, Acta Chem. Scand. 1973, 27, 888–890;
- 13bG. A. Kraus, M. J. Taschner, J. Org. Chem. 1980, 45, 1175–1176;
- 13cG. A. Kraus, B. Roth, J. Org. Chem. 1980, 45, 4825–4830;
- 13dB. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981, 37, 2091–2096;
- 13eJ. Hayashida, V. H. Rawal, Angew. Chem. 2008, 120, 4445–4448;
- 14K. Takeda, A. Akiyama, H. Nakamura, S. Takizawa, Y. Mizuno, H. Takayanagi, Y. Harigaya, Synthesis 1994, 1063–1066.
- 15S. Takano, K. Inomata, K. Samizu, S. Tomita, M. Yanase, M. Suzuki, Y. Iwabuchi, T. Sugihara, K. Ogasawara, Chem. Lett. 1989, 1283–1284.
- 16α-Methylenation of the crude aldehyde with Eschenmoser’s salt did not proceed in the absence of DBU.
- 17
- 17aA. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43, 2480–2482;
- 17bK. Omura, D. Swern, Tetrahedron 1978, 34, 1651–1660.
- 18
- 18aD. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156;
- 18bD. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7287.
- 19W. J. Elliott, J. Fried, J. Org. Chem. 1978, 43, 2708–2710 and references therein.
- 20The homochirality of γ-ketoester 24 and cycloadduct 28 was confirmed by HPLC on a chiral stationary phase column.
- 21For the use of α,α,α-trifluorotoluene as an effective solvent in RhII-catalyzed carbonyl ylide formation/1,3-dipolar cycloaddition reactions, see: S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N. Watanabe, S. Hashimoto, J. Am. Chem. Soc. 1999, 121, 1417–1418.
- 22T. Fukuyama, A. A. Laird, L. M. Hotchkiss, Tetrahedron Lett. 1985, 26, 6291–6292.
- 23For oxidative removal of a PMP group under buffered conditions, see: Y. Masaki, K. Yoshizawa, A. Itoh, Tetrahedron Lett. 1996, 37, 9321–9324.
- 24C. Visintin, A. E. Aliev, D. Riddall, D. Baker, M. Okuyama, P. M. Hoi, R. Hiley, D. L. Selwood, Org. Lett. 2005, 7, 1699–1702.
- 25J. H. Boyer, L. R. Morgan Jr., J. Org. Chem. 1961, 26, 1654–1656.
- 26The 1H NOE interactions of C7-H with C14-H and C18-H established the E stereochemistry of the major isomer.
- 27K. Freudenberg, H. H. Hubner, Chem. Ber. 1952, 85, 1181–1191.
- 28
- 28aS. W. Landvatter, J. A. Katzenellenbogen, J. Med. Chem. 1982, 25, 1300–1307;
- 28bT. Ohgiya, S. Nishiyama, Tetrahedron Lett. 2004, 45, 6317–6320.
- 29An attempt to use the aldehyde having a methanesulfonate at C16 instead of 38 b met with failure due to the poor solubility of the aldehyde at low temperature.
- 30T. Mukaiyama, M. Hayashi, Chem. Lett. 1974, 15–16. For a review, see:
- 31For the use of TMSOTf in Mukaiyama aldol-type reactions, see:
- 31aS. Murata, M. Suzuki, R. Noyori, J. Am. Chem. Soc. 1980, 102, 3248–3249;
- 31bS. Murata, M. Suzuki, R. Noyori, Tetrahedron 1988, 44, 4259–4275.
- 32Coupling product 45 a was obtained as a mixture of two diastereomers; the stereochemistry at C6 was verified by the 1H NOE correlation between C6-H and C11-H.
- 33Prolonged exposure of 45 a to DBU led to partial formation of (Z)-41 a, indicating that olefin isomerization occurs under basic conditions.
- 34Dimethyl acetal 44 b was prepared in 91 % yield from 4-hydroxy-3,5-dimethoxybenzaldehyde (46 b) by the following two-step sequence: 1) HC(OMe)3, TsOH, MeOH, reflux, 2.5 h; 2) Ac2O, Et3N, CH2Cl2, 12 h.
- 35J. Mulzer, M. Kappert, G. Huttner, I. Jibril, Angew. Chem. 1984, 96, 726–727;
- 36D. Ma, Z. Ma, Tetrahedron Lett. 1997, 38, 7599–7602.
- 37Optically pure (−)-47, [α]
=−37.3 (c=2.06 in CHCl3), was obtained from commercially available (−)-methyl (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate by using the Takacs procedure[38] in 77 % yield over two steps.
- 38J. M. Takacs, M. A. Helle, F. L. Seely, Tetrahedron Lett. 1986, 27, 1257–1260.
- 39Alcohol 48 was prepared from 4-methoxyphenol by the following two-step sequence: 1) NaH (1.1 equiv), 3-bromo-2-bromomethyl-1-propene (2.5 equiv), DMF, 1.5 h, 55 %; 2) In (1.2 equiv), HCHO (7.5 equiv), aq. THF, 48 h, 91 %.
- 40The beneficial effect of CH2Cl2 in base-mediated reactions finds precedent in our synthesis of zaragozic acids; see reference.[8l]
- 41In an effort to attain the equilibrium, isomers 49 a and ent-21 were enolized with NaN(TMS)2 (1 equiv) in THF at −78 °C, followed by treatment with sodium alkoxide derived from 48 (1.5 equiv) at −23 °C for 96 and 48 h, respectively. Nearly identical ratios (1:1.8 and 1:2, respectively) of isomers 49 a and ent-21 were obtained under these conditions.
- 42Compared with (E)-enoate (−)-47, the reaction of the corresponding (Z)-isomer 51[43] with alcohol 48 was extremely sluggish under the optimal conditions. Even after 144 h, a diastereomeric mixture of adducts 49 a and ent-21 was obtained in only 43 % yield in a ratio of 20.5:1, favoring the syn-isomer 49 a, and a 9:1 Z/E mixture of enoates 51 and (−)-47 was recovered.
- 43Preparation of ent-51 was reported previously, see: Z. Chilmonczyk, M. Egli, C. Behringcr, A. S. Dreiding, Helv. Chim. Acta 1989, 72, 1095–1106.
- 44
- 44aY. Wen, S. He, K. Xue, F. Cao, Zhong Cao Yao 1986, 17, 122;
- 44bK. Sun, X. Li, W. Li, J. Wang, J. Liu, Y. Sha, Chem. Pharm. Bull. 2004, 52, 1483–1486;
- 44cH.-B. Yin, Z.-S. He, Y. Ye, J. Nat. Prod. 2000, 63, 1164–1165.
- 45
- 45aB. B. Snider, J. F. Grabowski, Tetrahedron Lett. 2005, 46, 823–825;
- 45bB. B. Snider, J. F. Grabowski, Tetrahedron 2006, 62, 5171–5177.
- 46For recent reviews, see:
- 46aV. Singh, U. M. Krishna, Vikrant, G. K. Trivedi, Tetrahedron 2008, 64, 3405–3428;
- 46bH. Pellissier, Adv. Synth. Catal. 2011, 353, 189–218.
- 47For representative total syntheses of natural products through a [5+2] cycloaddition of oxypyrylium species, see:
- 47aP. A. Wender, H. Y. Lee, R. S. Wilhelm, P. D. Williams, J. Am. Chem. Soc. 1989, 111, 8954–8957;
- 47bP. A. Wender, F. E. McDonald, J. Am. Chem. Soc. 1990, 112, 4956–4958;
- 47cP. A. Wender, K. D. Rice, M. E. Schnute, J. Am. Chem. Soc. 1997, 119, 7897–7898;
- 47dP. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997, 119, 12976–12977;
- 47eF. López, L. Castedo, J. L. Mascareñas, Chem. Eur. J. 2002, 8, 884–899;
- 47fB. Tang, C. D. Bray, G. Pattenden, Tetrahedron Lett. 2006, 47, 6401–6404;
- 47gP. A. Roethle, P. T. Hernandez, D. Trauner, Org. Lett. 2006, 8, 5901–5904;
- 47hY. Li, C. C. Nawrat, G. Pattenden, J. M. Winne, Org. Biomol. Chem. 2009, 7, 639–640;
- 47iK. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 8219–8222.
- 48D. Jiang, C. Chiaro, P. Maddali, K. S. Prabhu, D. G. Peterson, J. Agric. Food Chem. 2009, 57, 9932–9943.
- 49Catalytic asymmetric synthesis of compounds 54 and 55 revealed that these natural products are also biosynthesized in near-racemic form; see references [8r, 8s].
- 50B. B. Snider, X. Wu, S. Nakamura, S. Hashimoto, Org. Lett. 2007, 9, 873–874.
- 51For a review on biomimetic total syntheses of natural products, see: P. G. Bulger, S. K. Bagal, R. Marquez, Nat. Prod. Rep. 2008, 25, 254–297.
